Cardiovascular disease remains one of the leading causes of death in the world. Its progression is part of the aging process. From mouse to man, one consistent feature of aging and cardiovascular disease is the stiffening of blood vessels. This elastic property is tantamount to blood vessels to effectively deliver blood to target organs. With progressive stiffening, end organ delivery of oxygen, nutrition, and molecular communication can lead to organ failure, dementia, and/or death. This age-dependent vascular dysfunction can lead to acute events, like heart attacks and strokes, which do exhibit a circadian rhythm in onset, but can also lead to progressive decline in cognitive function, which are also linked to circadian rhythm. The circadian clock, Bmal1, Clock, Per, and Cry, are expressed and oscillating in blood vessels and intimately connected with the aging of blood vessels. In Bmal1-KO mice, we have discovered that there is increased vascular stiffness in their blood vessels, suggesting that a broken clock may speed the aging of blood vessels, and age-dependent worsening of pathological vascular remodeling. We have also found that the disintegrin/metalloprotease ADAM17/TACE tracks uniquely with age in human blood vessels, and that it exhibits a circadian rhythm as do its outputs including TNF, IL6r, and F11r. In aorta of young mice, we have now found that Alzheimer Disease blood marker exhibits a circadian rhythm, a rhythm that is lost in old mice. The central hypothesis of this application is that dysfunction of circadian clock is a prime mediator of age-related impairment of arterial relaxation and elasticity, which we propose is through ADAM17 regulation, and as part of a supplemental application, we will extend our proposal to determine if these signals from the periphery can contribute to Alzheimer?s Disease pathology in mice. Three specific Aims are proposed. In specific aim 1 we will determine if a dysfunctional circadian clock mediates accelerated vascular dysfunction and arterial stiffening in aging. In specific aim 2, we will dissect the arterial wall-intrinsic and extrinsic mechanisms, which alter vascular clock and cause arterial stiffness in aging. In specific aim 3, we will examine the mechanisms through which circadian clock dysfunction leads to arterial aberrant ADAM17 signaling and vascular dysfunction in aging.